KR20130078101A - Fixed dose combination formulation comprising losartan, amlodipine and hydrochlorothiazide - Google Patents

Abstract

PURPOSE: A fixed-dose combination formulation containing losartan, amlodipine, and hydrochlorothiazide with excellent release rate and stability for preventing or treating cardiovascular diseases is provided to minimize side effects and to prevent or treat cardiovascular diseases with product stability. CONSTITUTION: A fixed-dose combination formulation for preventing or treating cardiovascualr diseases contains losartan or a pharmaceutically acceptable salt thereof; amlodipine or a pharmaceutically acceptable salt thereof; and hydrochlorothiazide. Each active ingredient is separately filled in a capsule. A method for manufacturing the fixed-dose combination formulation comprises the steps of: mixing or granulating losartan or the pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient, and tableting to obtain a losartan tablet part; mixing or granulating amlodipine or the pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient, and tableting to obtain an amlodipine tablet part; mixing or granulating hydrochlorothiazide and a pharmaceutically acceptable excipient, and tableting to obtain a hydrochlorothiazide tablet part; and filling same soft capsules with each tablet part. [Reference numerals] (AA) Losartan tablet; (BB) Amlodipine tablet; (CC) Hydrochlorothiazide tablet

Description

FIXED DOSE COMBINATION FORMULATION COMPRISING LOSARTAN, AMLODIPINE AND HYDROCHLOROTHIAZIDE}

The present invention relates to fixed dose combination formulations for the prophylaxis or treatment of cardiovascular diseases, including lozatan, amlodipine and hydrochlorothiazide, which have excellent dissolution rates and stability.

Hypertension is classified into essential hypertension and secondary hypertension. Most of the hypertension, that is, 90 to 95% is an essential hypertension of unknown cause. The treatment of hypertension can be treated by removing the cause of secondary hypertension, but in the case of essential hypertension, the cause is not known exactly, so the treatment of stabilization, diet, exercise, etc. is performed. If it doesn't work, you will be given a combination of medications.

Drugs commonly used in the treatment of hypertension are broadly divided into vasodilators, diuretics, and sympathetic inhibitors according to the mechanism of action of the drug, and currently widely used vasodilators, depending on the mechanism of action, angiotensin converting enzyme (ACE) inhibitor, angiotensin II receptor blockers and calcium channel blockers.

It is important to keep your blood pressure in a normal range rather than to treat the blood pressure itself, so it is important to prevent cardiovascular complications such as coronary artery disease such as life-threatening stroke, heart failure and myocardial infarction, and kidney failure. It is important to control your blood pressure. As such, blood pressure medications are required to be taken for a long time, so be careful when selecting a therapeutic drug. Therefore, rather than selecting one drug for continuous treatment, the combination of drugs with different mechanisms can be used together to provide a better prophylactic and therapeutic effect, and can be caused by prolonged drug intake by reducing the use of a single drug in combination administration. It is necessary to reduce the side effects that are present. The high blood pressure medical guideline (JNC7) also suggests that a combination of different mechanisms is recommended if a single agent is not sufficient to control blood pressure.

However, in the case of combined administration, the medication prescribed in two or more individual dosage units may reduce the medication compliance of the patient, which may cause a great inconvenience for hypertensive patients who require continuous blood pressure management. In addition, multiple individual unit medications should be taken at a single dose, and the fact that several individual unit medications should be carried at all times may also cause great discomfort to patients with hypertension who have to continue their social life.

In order to alleviate these shortcomings, various developments and studies on fixed dose combination drugs (FDCs) of specific active ingredients have recently been made. By "fixed dose combination" drug or formulation is meant a combination of two or more drugs or active ingredients present in a single dosage unit such as a tablet or capsule. In contrast, the term “free dose combination” drug or formulation as used herein refers to a combination of two or more drugs or active ingredients administered simultaneously, but as two or more dosage units. However, fixed dose combination formulations of such specific active ingredients are not easy to develop for the following reasons.

First, when formulating a fixed dose combination dosage composition, the fixed dose combination dosage formulation composition may provide a biologically equivalent effect or a better pharmacodynamic effect than the corresponding individual free dose combination of the same active ingredient. Hard. This is because the development of fixed dose combination dosage forms can cause unexpected problems due to the pharmacokinetic and pharmaceutical properties of the drug to be formulated.

For example, lojatan has a low absolute oral bioavailability in the range of about 25-35%. This results in a very good dissolution pattern when lojatan is eluted at relatively high pH such as purified water and pH 6.8, but at low pH (e.g., pH 1.2, pH 2.0), etc., which corresponds to the gastrointestinal pH at which the drug is mainly absorbed. The gelling is characterized by eluting very slowly, the commercially available Rozatan formulation Coza (Cozaar) also has a problem that the dissolution rate of the initial 30 minutes at pH 1.2 to 2.0 is less than 30%. Due to the characteristics of rozatan, when a fixed dose combination formulation with amlodipine or hydrochlorothiazide is developed, a problem is caused that amlodipine or hydrochlorothiazide is trapped inside the gel and the elution is lowered by gelation of rozatan.

In addition, hydrochlorothiazide is characterized by low solubility and low in vivo absorption (BCS Class IV, low solubility, low biopermeability), so that the change in bioavailability is very large even when administered as an individual unit. Development of fixed dose combination formulations with is difficult.

As another problem, stability is likely to be lowered due to the interactivity between different active ingredients. In particular, when combining compounds that are difficult to handle, development of fixed dose combination dosage forms in physicochemically stable form is more difficult.

For example, amlodipine formulations are typically made by combining amlodipine, a constituent that exhibits efficacy, with a salt that aids in the activation and formulation of the drug. The salt is a part which helps stabilize the amlodipine which is an active ingredient, and it is useful that the amlodipine is in the free base form, but is preferably administered in the form of a salt with a pharmaceutically acceptable acid because of its low solubility in water.

It is known that such acid addition salts of amlodipine, for example, amlodipine maleate salts, can be decomposed into amlodipine aspartate of Formula 1 or amlopyridine of Formula 2, etc., over time when formulated (US Patent 6,919,087). Due to such a decomposition reaction, the pharmaceutical composition containing amlodipine maleate salt has a problem of poor stability.

[Formula 1]

[Formula 2]

Due to this problem of deterioration of stability, the amlodipine besylate salts disclosed in EP 244 944 (corresponding US Patent No. 4,879,303) are mainly used for tablets currently on the market. However, the amlodipine besylate salt is also smaller than the amlodipine maleate salt, but causes a decomposition reaction to various decomposition products, and thus, the pharmaceutical composition including the same has a problem that the stability decreases and the drug efficacy decreases with time. Have

Accordingly, the present inventors have developed and formulated a camsylate salt having better physical properties such as solubility and stability than amlodipine besylate salt and marketed it as a product called amodipin. Surprisingly, however, it has been found that even the most stable amlodipine camsylate salt, when formulated in combination with rozatan, breaks down into a variety of products, unlike in amlodipine single formulations. This is because the physical properties of amlodipine itself are unstable to light and humidity, and it may be very difficult to secure stability of amlodipine when a fixed dose combination formulation with other pharmaceutically active substances, such as rozatan and hydrochlorothiazide, is made. Further, in general, if the thermal stability is applied in the losartan potassium salt, too acidic conditions known to be satisfactory degradation products E, it is already known that the named polymerization to form F i (Z.Zhao such as, J. Pharm. Biomed. Anal , 20: 129-136, 1999). In the case of hydrochlorothiazide, it is easily decomposed into benzothiadiazine analog A over time.

Therefore, the inventors of the present invention while studying to prepare a fixed dose combination formulation of rozatan, amlodipine and hydrochlorothiazide for the prevention and treatment of cardiovascular diseases, all three components are prepared in a separate separation layer and then filled into capsules The present invention was completed by confirming that the bioequivalence with a single product can be secured, and that stability and medication compliance can be improved.

Accordingly, it is an object of the present invention to provide a fixed dose combination formulation for the prevention or treatment of cardiovascular diseases with excellent dissolution rate and stability, containing lozatan, amlodipine and hydrochlorothiazide with different mechanisms of action.

In order to achieve the above object, the present invention, the active ingredient, losartan (losartan) or a pharmaceutically acceptable salt thereof; Amlodipine or a pharmaceutically acceptable salt thereof; And hydrochlorothiazide (hydrochlorothiazide), and the active ingredients are each provided in a separate separation layer to provide a fixed dose combination formulation for the prevention or treatment of cardiovascular diseases, filled in capsules.

Fixed dose combination formulations according to the present invention can minimize side effects compared to conventional single agents and combinations, and the dissolution rate is excellent biologically equivalent or superior to each single product, as well as excellent product stability over time, cardiovascular It can be usefully used for the prevention or treatment of related diseases.

1 is a schematic representation of a fixed dose combination formulation of lozatan, amlodipine and hydrochlorothiazide according to the present invention.
2 is a graph showing the dissolution rate of hydrochlorothiazide as a result of Test Example 1.
3 is a graph showing the dissolution rate of amlodipine as a result of Test Example 1.

The present invention provides an active ingredient, losartan or a pharmaceutically acceptable salt thereof; Amlodipine or a pharmaceutically acceptable salt thereof; And hydrochlorothiazide (hydrochlorothiazide), the active ingredient is a fixed dose combination formulation for the prevention or treatment of cardiovascular diseases, each of which is filled in a capsule in a separate separation layer.

Lozatan is 2-butyl-4-chloro-1-[[2 '-(1H-tetrazol-5-yl) [1,1'-biphenyl] -4-yl] methyl] -1H-imidazole- Common name for 5-methanol; US Pat. No. 5,608,075; 5,138,069; 5,153,197 and the like. In particular, rozatan potassium is currently sold under the trade name Cozaar. Thus, the preferred pharmaceutically acceptable salt of rozatan of the present invention is rozatan potassium. Lozatan prevents angiotensin II, a vasoconstrictor, from binding to its receptors to treat hypertension and heart failure, to treat ischemic peripheral circulation, myocardial ischemia (angina), prevent the progression of heart failure after myocardial infarction, and diabetic It is used to treat neuropathy and glaucoma. The daily dose of rojatan or a pharmaceutically acceptable salt thereof is 0.1-500 mg, preferably 1-200 mg, more preferably 25-200 mg as rozatan.

Amlodipine is 3-ethyl-5-methyl-2- (2-aminoethoxy-methyl) -4- (2-chlorophenyl) -6-methyl-1,4-dihydro-3,5-pyridine dicarboxyl The pharmaceutically acceptable salt of amlodipine used in the present invention, which is a generic name for the rate, is formed from an acid forming a nontoxic acid addition salt containing a pharmaceutically acceptable anion, for example hydrochloride, hydrobromide, sulfate , Phosphates, acetates, maleates, fumarates, lactates, tartrates, citrates, gluconates, besylates and camsylates, and the like, but is not limited thereto. Among these, amlodipine besylate salt is sold under the trade name Novasc, and a chamlate salt having better physical properties such as solubility and stability than besylate salt is disclosed in Korean Patent No. 4452491. Accordingly, amlodipine camsylate is most preferred as a pharmaceutically acceptable salt of amlodipine of the present invention. Amlodipine is a long-acting calcium channel blocker in the human body and is useful for the treatment of cardiovascular diseases such as angina, hypertension and congestive heart failure. The daily dose of amlodipine or a pharmaceutically acceptable salt thereof is 0.5-20 mg, preferably 1-10 mg, more preferably 2.5-10 mg as amlodipine.

Hydrochlorothiazide is the common name of 6-chloro-1,1-dioxy-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide, currently sold under various trade names It is becoming. Hydrochlorothiazide is a thiazide diuretic that acts mainly in the distal tubule and reduces sodium reabsorption by inhibiting the sodium / chlorine cotransporter of the tubular membrane. As a result, increasing the concentration of sodium and chlorine in the tubular fluid causes diuresis with an increase in the excretion of sodium and chlorine. Therefore, it is clinically used for the treatment of hypertension, heart failure, hypercalciuria, diabetes insipidus. The daily dose of hydrochlorothiazide is 1-100 mg, preferably 3-50 mg, more preferably 6.25-25 mg.

Fixed dose combination formulations comprising rozatan or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof and hydrochlorothiazide can be used for the prevention or treatment of cardiovascular diseases. Cardiovascular diseases include, but are not limited to, angina pectoris, hypertension, arterial spasm, deep vein, cardiac hypertrophy, cerebral infarction, congestive heart failure, myocardial infarction, and the like. Fixed dose combination formulations comprising rozatan or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof and hydrochlorothiazide have a superior effect on the prevention or treatment of cardiovascular diseases than conventional single agents. It has the advantage of reducing the side effects of each of the drugs used and to increase the compliance of the patient. However, due to the differences in the physical properties inherent in rozatan, amlodipine and hydrochlorothiazide, the following problems arise when simple combinations are made of fixed dose combination formulations.

The first problem is the gelation of rojatan. Lojatan shows a very good elution pattern when eluted at relatively high pH, such as purified water and pH 6.8, but gels at low pH (e.g., pH 2.0, pH 1.2, etc.) and elutes very slowly. This phenomenon has a great effect on the dissolution rate of the preparation in that the organ that disintegrates and dissolves first when taking oral preparations has a low pH, and may also affect absorption in vivo. In addition, as lozatan gels in the composition, the amlodipine and the hydrochlorothiazide included together are trapped inside the gel, and elution is lowered. This phenomenon can also be confirmed in the dissolution rate graphs of FIGS. 2 and 3 obtained in Test Example 1. That is, a tablet simply mixing the two components shows a result that is far short of the "release time point of 30 minutes, 80% dissolution rate" of the immediate release type of the single amlodipine formulation and the single hydrochlorothiazide formulation. These results show that fixed dose combination formulations of rozatan, amlodipine and hydrochlorothiazide prepared by simple mixing methods may not be able to secure bioequivalence with free dose combination formulations. Therefore, there is a need for the development of a fixed dose combination formulation of three active ingredients, even under low pH conditions, without elution due to gelation of rozatan.

The second problem is that when the complex formulation of rozatan, amlodipine, and hydrochlorothiazide is prepared by complex mixing, the formation of impurities under accelerated conditions increases the stability of the formulation. This may be because the physicochemical reactions between lozatan, amlodipine and hydrochlorothiazide affect the stability of each active ingredient.

In order to solve this problem, a method of stabilizing the active ingredient by optimizing the pH of the composition by adding an acid or an alkalizing agent may be considered, but even in this case, amlodipine having an ester bond in the molecule is easily hydrolyzed and acidic under alkaline conditions. Under the conditions, there is a problem that rotan is susceptible to decomposition products. Indeed, as disclosed in US Pat. No. 6,919,087, even when the pH of the composition comprising the excipient was adjusted to 5.5 to 7.0, the amlodipine-rozatan combination formulation did not exhibit sufficient stability.

In order to improve this, it is possible to try to separate drugs using a two-layer tablet press or a three-layer tablet press, but not only requires a special production facility called a double-layer tablet or a three-layer tablet press, but also a reaction at each layer contact. Since there may be, 100% separation of the active ingredient in each layer is mechanically impossible.

Thus, in order to minimize the dissolution rate of amlodipine and hydrochlorothiazide due to gelation of rojatan, each drug ensures its natural dissolution and stability to maximize clinical utility, so that the present invention is rozatan or its Pharmaceutically acceptable salts, amlodipine or a pharmaceutically acceptable salt thereof and hydrochlorothiazide form a separate layer separate from each other to provide a fixed dosage combination formulation in the form of a capsule filled. Since the formulations of the present invention are physically separated from each drug component, it is easy to secure bioequivalence, has excellent stability, and can separately remove the reactivity between each active ingredient because it is produced separately. By minimizing the mass of the excipients used in the preparation of each independent layer, the size of the dosage form to be administered can be reduced, and thus the medication compliance is very excellent compared to the conventional composite agent. In addition, it can alleviate the side effects of existing single agents and combinations and at the same time can exhibit an improved preventive and therapeutic effect of cardiovascular diseases.

In one embodiment, lozatan, amlodipine and hydrochlorothiazide in the fixed dose combination formulations of the present invention are each filled into capsules in separate separation layers, which may have a tablet form. In a specific embodiment, the fixed dose combination formulation of the present invention comprises a tablet consisting of rozatan or a pharmaceutically acceptable salt thereof, a tablet consisting of amlodipine or a pharmaceutically acceptable salt thereof and a tablet consisting of hydrochlorothiazide It may be a capsule.

The rozatan, amlodipine and hydrochlorothiazide tablets are subjected to a compression process in a tablet press in the form of a mixture or granule with a pharmaceutically acceptable excipient, respectively, wherein the tablets have varying hardness depending on the tablet pressure of the tablet press. According to the tableting pressure during tableting, even if the composition of the same mass shows various densities, it can be obtained in the form of tablets having a density of generally 0.8 g / ml or more. The form of the tablet thus obtained can be generally selected in the form of round, rectangular, oval tablets, but generally in the form of circular tablets in consideration of the filling into the capsule is preferred. The diameter of the tablets exhibiting a circular shape is preferably 1 mm to 7 mm, more preferably 2 mm to 6 mm. If the diameter of the tablet is large, the capsule size used for filling the tablet may increase, which may cause discomfort.If the diameter of the tablet is small, the tablet may not only have a limit on the mass that can be tableted, but also have low tabletability. There is a disadvantage that the work speed is lowered.

In the fixed dose combination formulations of the present invention, one or more of the tablets present as separate separation layers may be coated with a polymer film coating layer. Pharmaceutically acceptable polymers used in the film coating layer include methyl cellulose, ethyl cellulose, polyvinyl alcohol, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, etc., but may form a film coating. Any conventional polymer can be used. The amount of polymer to be used is preferably kept to a minimum to provide an optimal formulation size and for effective preparation, with about 1 to about 20 wt%, preferably about 2 to about 10 wt% being suitable for the total weight of the formulation. Do.

In the fixed dose combination formulations of the present invention, separate separation layers each comprising rozatan or a pharmaceutically acceptable salt thereof, amlodipine or a pharmaceutically acceptable salt thereof and hydrochlorothiazide as the active ingredient are pharmaceutically acceptable in addition to the active ingredient. Excipients may be included. Such pharmaceutically acceptable excipients include pharmaceutically acceptable diluents, pharmaceutically acceptable disintegrants, pharmaceutically acceptable binders, pharmaceutically acceptable stabilizers, pharmaceutically acceptable glidants and pharmaceutically acceptable pigments, and the like. Can be. In the fixed dose combination formulations of the present invention, the active ingredient and the pharmaceutically acceptable excipient may be used in a weight ratio of 1: 0.25 to 1:20.

Examples of pharmaceutically acceptable diluents include microcrystalline cellulose, lactose, rudipress, mannitol, calcium dihydrogen phosphate, starch, low-substituted hydroxypropyl cellulose and mixtures thereof. The diluent may be used in an amount ranging from about 5 to about 95 weight percent, preferably from about 10 to about 85 weight percent, based on the total weight of the formulation. On the other hand, the diluent may preferably be a water-soluble diluent. When such diluents are used, the ratio of active ingredient and diluent contained in the separate separation layer is very important. Water-soluble diluents are soluble in water during elution, such as lactose, ludipress (excipients with lactose, crospovidone, povidone (93: 3.5: 3.5, w / w (%))), mannitol, sorbitol, etc. Excipients, for example, when mixed with rojatan as the active ingredient, dissolution rate can be maximized when mixed in a constant weight ratio. This is because of the physical properties of rozatan gelled at low pH, because the rotantan layer can exhibit a rapid disintegration rate when the weight ratio of rozatan and water-soluble diluent is optimized. The weight ratio of the lojatan to the water-soluble diluent is preferably from 1: 0.1 to 1:40, more preferably from 1: 0.25 to 1:20.

On the other hand, as a method for producing granules used for tableting of the rotantan layer, it is advantageous to make a simple mixed or dry granule manufacturing method using no water and an organic solvent in terms of stability of rozatan. Surprisingly, when the moisture value of the rojatan layer is too high, it was confirmed that the stability of rojatan deteriorates sharply, which may be due to the hydrolysis or change of properties due to the high water solubility of the rojatan. In the present invention, the water content of the excipient used in the rozatan layer is preferably within 5%, more preferably within 3%.

In addition, specific examples of disintegrants that may be used in the fixed dose combination formulations of the present invention include crospovidone, sodium starch glyconate, croscarmellose sodium, low-substituted hydroxypropylcellulose, starch, alginic acid or its sodium salt, and And mixtures thereof. Preferably crospovidone, sodium starch glyconate, croscarmellose sodium, low-substituted hydroxypropyl cellulose or mixtures thereof may be used, more preferably crospovidone and sodium starch glyconate may be used. Disintegrants may be used in amounts ranging from about 1 to about 30 weight percent, preferably from about 2 to about 15 weight percent, based on the total weight of the composition.

In addition, specific examples of binders that can be used in the fixed dose combination formulation of the present invention include hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, copovidone, macrogol, hard silicic anhydride, synthetic aluminum silicate, silicic acid Silicate derivatives such as calcium or magnesium metasilicate aluminate, phosphates such as calcium hydrogen phosphate, carbonates such as calcium carbonate, and mixtures thereof.

In addition, specific examples of stabilizers that may be used in the fixed dose combination formulations of the present invention include antioxidants. The use of antioxidants can increase the stability of the active ingredient, in particular amlodipine, and reduce the deformation of the active ingredient with temperature and moisture, thereby increasing the stability over time. Specific examples of the antioxidants include butylated hydroxy toluene (BHT), butylated hydroxy anisole (BHA), ascorbic acid, ascorbyl palmitic acid, ethylenediaminetetraacetic acid (EDTA), sodium pyrosulfite And mixtures thereof. In particular, butylated hydroxy toluene is preferred.

Specific examples of glidants that may be used in the fixed dose combination formulations of the present invention also include metal stearates such as stearic acid, calcium stearate or magnesium stearate, talc, colloidal silica, sucrose fatty acid esters, hydrogenated vegetable oils. And waxes of high melting point, glyceryl fatty acid esters, glycerol dibehenate and mixtures thereof.

The capsules used in the fixed dose combination formulations of the present invention can be used as the general hard capsules used in medicine. Hard capsules are gelatin capsules, hypromellose capsules, pullulan capsules (NP caps ^TM , Capsugel, etc.), polyvinyl alcohol, etc., according to the type of the base constituting the rozatan, amlodipine and hydrochlorothia Gelatin capsules are preferred when the initial dissolution rate is important, such as a fixed dose combination formulation of zayed.

The capsule size of the hard capsules used in the fixed dose combination formulations of the present invention may be any of the general capsule sizes used in medicine. The capsule size has various internal volumes depending on the number of capsules, and considering the convenience of the patient's medication taking the combination formulation of the present invention, the capsule size is more preferable. However, it is desirable to select an appropriate capsule size due to the mass limits of the contents to be filled in the capsule. The size of the hard capsules usable in the formulation of the present invention is preferably 0, 1, 2, 3 or 4 capsules. A schematic diagram of the fixed dose combination formulations described above is shown in FIG. 1.

In the fixed dose combination formulations of the present invention, as shown in FIGS. 2 and 3, the dissolution rate of amlodipine or its pharmaceutically acceptable salts and hydrochlorothiazide reaches at least 80% within 30 minutes after the start of the dissolution test.

The present invention also provides a process for preparing a rozatan tablet by a) mixing or granulating rojatan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient; b) mixing or granulating amlodipine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and then tableting to obtain an amlodipine tablet; c) mixing or granulating the hydrochlorothiazide and the pharmaceutically acceptable excipient and then tableting to obtain a hydrochlorothiazide tablet; And d) filling the rojatan tablets, amlodipine tablets and hydrochlorothiazide tablets into the same hard capsules, thereby providing a fixed dose combination formulation for preventing or treating cardiovascular diseases. One or more steps of a) to c) of the above method may further comprise coating the obtained tablet with a pharmaceutically acceptable polymer.

The fixed dose combination formulation of the present invention has an excellent dissolution rate of rozatan, amlodipine, and hydrochlorothiazide at a level equivalent to that of a commercially available single agent, and is excellent in stability according to time-varying changes due to very little change in the soft substance during the harsh test. Therefore, the formulation of the present invention can be usefully used in cardiovascular diseases such as angina pectoris, hypertension, arterial spasm, deep vein, cardiac hypertrophy, cerebral infarction, congestive heart failure, myocardial infarction and the like.

Hereinafter, the present invention will be described in detail based on the following examples. However, the following examples are only for illustrating the present invention and the scope of the present invention is not limited thereto.

Example 1 Preparation of Fixed Dose Combination Formulations I

Rosatan-containing layer

Potassium lozatan 50.0 mg

Rudipress 15.7 mg

Copovidone 3.0 mg

Light anhydrous silicic acid 0.5 mg

Microcrystalline cellulose 10.0 mg

Magnesium Stearate 0.8 mg

Opadry Y-1-7000 2.4 mg

Purified water (12.0 mg)

Amlodipine-containing layer

7.84 mg of amlodipine camsylate (5 mg as amlodipine)

Microcrystalline Cellulose 43.76 mg

D-mannitol 14.0 mg

Sodium starch glycolate 1.7 mg

Hydroxypropylcellulose 2.0 mg

0.7 mg magnesium stearate

Purified water (35.0 mg)

Opadry Y-1-7000 2.1 mg

Purified water (11.0 mg)

Hydrochlorothiazide-containing layer

Hydrochlorothiazide 12.5 mg

Microcrystalline Cellulose 38.80 mg

Mannitol 13.0 mg

Sodium starch glycolate 3.0 mg

Hydroxypropylcellulose 2.0 mg

0.7 mg magnesium stearate

Purified water (35.0 mg)

Opadry Y-1-7000 2.1 mg

Purified water (11.0 mg)

The powder corresponding to the lojatan-containing layer was mixed. After rotamane mixture was compressed using a round punch having a diameter of 5 mm, 50 mg tablets of lozatan were coated using a solution of Opadry Y-1-7000 (color cone) dissolved in purified water as a coating solution.

In addition, using a binder solution of 2.0 mg of hydroxypropyl cellulose in 35.0 mg of purified water per unit tablet in the composition corresponding to the amlodipine-containing layer, the granulated powder of the remaining excipients was granulated, dried to 20 mesh and dried to obtain granule powder. . After the granulation powder was compressed, amlodipine 5 mg tablet was coated by using Opadry Y-1-7000 in purified water as a coating solution.

In addition, after tableting in the same manner as amlodipine tablets and coated to prepare a 12.5 mg hydrochlorothiazide tablets.

The three tablets were filled into Hard Capsule No. 2 to complete a fixed dose combination formulation of 50 mg rozatan, 5 mg amlodipine and 12.5 mg hydrochlorothiazide. The mass sum of the three tablets filled in the hard capsule was 226.6 mg, which was confirmed to be very small.

Example  2: Preparation of Fixed Dose Combination Formulations II

Rosatan-containing layer

Potassium lozatan 50.0 mg

Rudipress 15.7 mg

Copovidone 3.0 mg

Light anhydrous silicic acid 0.5 mg

Microcrystalline cellulose 10.0 mg

Magnesium Stearate 0.8 mg

Hypromellose 1.6 mg

0.4 mg of hydroxypropyl cellulose

Titanium oxide 0.36 mg

Talc 0.04 mg

Purified water (28.0 mg)

Amlodipine-containing layer

7.84 mg of amlodipine camsylate (5 mg as amlodipine)

22.5 mg of microcrystalline cellulose

D-mannitol 7.26 mg

Sodium starch glycolate 0.85 mg

Hydroxypropylcellulose 1.15 mg

0.4 mg magnesium stearate

Purified water (20.0 mg)

Hypromellose 0.8 mg

0.2 mg of hydroxypropyl cellulose

Titanium oxide0.18 mg

Iron Oxide 0.01 mg

Talc 0.01 mg

Purified water (14.0 mg)

Hydrochlorothiazide-containing layer

Hydrochlorothiazide 12.5 mg

Microcrystalline cellulose 18.5 mg

Mannitol 5.95 mg

Sodium starch glycolate 1.5 mg

Hydroxypropylcellulose 1.15 mg

0.4 mg magnesium stearate

Purified water (20.0 mg)

Hypromellose 0.8 mg

0.2 mg of hydroxypropyl cellulose

Titanium oxide0.18 mg

Red Iron Oxide 0.01 mg

Talc 0.01 mg

Purified water (14.0 mg)

Using the same method as in Example 1 as described above to prepare a coating tablets of lozatan, amlodipine and hydrochlorothiazide, and then filled into hard capsule No. 2, 50 mg lozatan, 5 mg amlodipine and hydrochlorothiazide A fixed dose combination formulation of 12.5 mg was completed. The mass sum of the three tablets filled in the hard capsule was found to be very small (164.8 mg).

Example  3: Preparation of Fixed Dose Combination Formulations III

Rosatan-containing layer

Potassium lozatan 50.0 mg

Rudipress 15.7 mg

Copovidone 3.0 mg

Light anhydrous silicic acid 0.5 mg

Microcrystalline cellulose 10.0 mg

Magnesium Stearate 0.8 mg

Hypromellose 1.6 mg

0.4 mg of hydroxypropyl cellulose

Titanium oxide 0.36 mg

Talc 0.04 mg

Purified water (28.0 mg)

Amlodipine-containing layer

7.84 mg of amlodipine camsylate (5 mg as amlodipine)

22.5 mg of microcrystalline cellulose

D-mannitol 7.26 mg

Sodium starch glycolate 0.85 mg

Hydroxypropylcellulose 1.15 mg

0.4 mg magnesium stearate

Purified water (20.0 mg)

Hypromellose 0.8 mg

0.2 mg of hydroxypropyl cellulose

Titanium oxide0.18 mg

Iron Oxide 0.01 mg

Talc 0.01 mg

Purified water (14.0 mg)

Hydrochlorothiazide-containing layer

Hydrochlorothiazide 25.0 mg

Microcrystalline Cellulose 37.0 mg

Mannitol 11.9 mg

Sodium starch glycolate 3.0 mg

Hydroxypropylcellulose 2.3 mg

0.8 mg magnesium stearate

Purified water (40.0 mg)

Hypromellose 1.6 mg

0.4 mg of hydroxypropyl cellulose

Titanium oxide 0.36 mg

Red Iron Oxide 0.02 mg

Talc 0.02 mg

Purified water (28.0 mg)

Using the same method as in Example 1 as described above to prepare a coating tablets of lozatan, amlodipine and hydrochlorothiazide, and then filled into hard capsule No. 2, 50 mg lozatan, 5 mg amlodipine and hydrochlorothiazide A 25 mg fixed dose combination formulation was completed. The mass sum of the three tablets filled in the hard capsule was found to be very small at 206 mg.

Example  4: Preparation of Fixed Dose Combination Formulations IV

Rosatan-containing layer

Potassium lozatan 50.0 mg

Rudipress 15.7 mg

Copovidone 3.0 mg

Light anhydrous silicic acid 0.5 mg

Microcrystalline cellulose 10.0 mg

Magnesium Stearate 0.8 mg

Hypromellose 1.6 mg

0.4 mg of hydroxypropyl cellulose

Titanium oxide 0.36 mg

Talc 0.04 mg

Purified water (28.0 mg)

Amlodipine-containing layer

15.68 mg (10 mg as amlodipine)

Microcrystalline cellulose 15.0 mg

D-mannitol 14.52 mg

Sodium starch glycolate 1.7 mg

Hydroxypropylcellulose 2.3 mg

0.8 mg magnesium stearate

Purified water (40.0 mg)

Hypromellose 1.6 mg

0.4 mg of hydroxypropyl cellulose

Titanium oxide 0.36 mg

Iron Oxide 0.02 mg

Talc 0.02 mg

Purified water (28.0 mg)

Hydrochlorothiazide-containing layer

Hydrochlorothiazide 12.5 mg

Microcrystalline cellulose 18.5 mg

Mannitol 5.95 mg

Sodium starch glycolate 1.5 mg

Hydroxypropylcellulose 1.15 mg

0.4 mg magnesium stearate

Purified water (20.0 mg)

Hypromellose 0.8 mg

0.2 mg of hydroxypropyl cellulose

Titanium oxide0.18 mg

Red Iron Oxide 0.01 mg

Talc 0.01 mg

Purified water (14.0 mg)

As described above, using the same method as in Example 1 to prepare a coating tablets of lozatan, amlodipine and hydrochlorothiazide, and then filled into hard capsule No. 2, 50 mg of lozatan, 10 mg of amlodipine and hydrochlorothiazide A fixed dose combination formulation of 12.5 mg was completed. The mass sum of the three tablets filled in the hard capsule was found to be very small at 206 mg.

Comparative example  1: Preparation of Fixed Dose Combination Formulations V (Simple Mixed Tablets)

Potassium lozatan 50.0 mg

7.84 mg of amlodipine camsylate (5 mg as amlodipine)

Hydrochlorothiazide 12.5 mg

Rudipress 15.7 mg

Copovidone 3.0 mg

Light anhydrous silicic acid 0.5 mg

Microcrystalline cellulose 92.56 mg

Mannitol 27.0 mg

Sodium starch glycolate 4.7 mg

Hydroxypropylcellulose 4.0 mg

Magnesium Stearate 2.2 mg

Rozatan, amlodipine, hydrochlorothiazide and excipients were mixed and compressed together in the composition of Comparative Example 1 to obtain a fixed dose combination formulation of 50 mg of lozatan, 5 mg of amlodipine and 12.5 mg of hydrochlorothiazide.

Comparative example  2: Preparation of Fixed Dose Combination Formulations VI  (Simple Mix Capsule)

Potassium lozatan 50.0 mg

7.84 mg of amlodipine camsylate (5 mg as amlodipine)

Hydrochlorothiazide 12.5 mg

Rudipress 15.7 mg

Copovidone 3.0 mg

Light anhydrous silicic acid 0.5 mg

Microcrystalline cellulose 92.56 mg

Mannitol 27.0 mg

Sodium starch glycolate 4.7 mg

Hydroxypropylcellulose 4.0 mg

Magnesium Stearate 2.2 mg

Rozatan, amlodipine, hydrochlorothiazide and excipients were mixed together in the composition of Comparative Example 1, and then filled into No. 1 hard capsules, and a fixed dose combination formulation of rozatan 50 mg, amlodipine 5 mg and hydrochlorothiazide 12.5 mg Obtained.

Test Example  One: Amlodipine  And Hydrochlorothiazide  Dissolution test

Elution under the following conditions using fixed dose combination formulations prepared in Examples 1 and 2, and fixed dose combination formulations prepared in Comparative Examples 1 and 2, dichroic tablets (Limited), and Novask tablets The test was conducted and compared.

-Dissolution condition-

Eluent: 0.01N HCl 900mL (pH 2.0)

Device: USP Paddle Method, 75rpm

Temperature: 37 ℃

-Analysis condition-

Column: A column packed with a 5 μm octadecylsilylated silica gel in a stainless tube about 4.6 mm in diameter and 25 cm in length.

Mobile phase: 0.015M potassium dihydrogen phosphate: acetonitrile: methanol

        (47: 32: 23, v / v)

Detector: ultraviolet absorption photometer (wavelength 238nm)

Flow rate: 1.2 mL / min

Injection volume: 20 uL

Column temperature: 40 ℃

- Criteria -

The elution rate is over 80% at 30 minutes.

- result -

As shown in FIGS. 2 and 3, in the case of fixed dose combination formulations in which lozatan, amlodipine, and hydrochlorothiazide of Example 1 and Example 2 were all separated, a simple mixed preparation Comparative Example 1 and Comparative Example 2 Compared with the high dissolution rate, both hydrochlorothiazide and amlodipine showed good dissolution patterns satisfying the criterion. On the other hand, in Comparative Example 1 and Comparative Example 2 prepared by simple mixing, both hydrochlorothiazide and amlodipine did not satisfy the criterion.

Test Example   2: severe storage stability test

The fixed dose combination formulations obtained in Examples 1 and 2 and the fixed dose combination formulations prepared in Comparative Examples 1 and 2 were subjected to harsh storage tests for light and heat under the following conditions, and then rozatan, amlodipine, and hydrochloro The degree of change of analogue due to thiazide was evaluated to compare the stability. The results are shown in Table 3 below.

-Photostability Chamber Condition (Light Severity Condition)-

(1) Device name: Xe-3-HC from Q-Lab

(2) Temperature and humidity: 25 ℃ ± 2 ℃ / 60% ± 5% RH

(3) Illumination: 0.80W / m ² / nm, 18.44 hours

          (1.2 million lux, photostability test conditions presented in ICH guidelines)

(4) Sample: Petri Dish Storage

Test Point-after initial exposure and light exposure (after 1.2 million lux exposure)

Severe Stability Chamber Conditions (Heat Severe Conditions)

(1) Temperature and humidity: 50 ℃ ± 2 ℃

(2) Sample: HDPE Bottle Packing

At the time of testing-after initial and 28 days storage

Analytical Conditions (Flexibles from Rozatan and Amlodipine)

Column: Column filled with octadecylsilylated silica gel for liquid chromatograph with a particle diameter of 5 μm in a stainless tube with an inner diameter of about 4.6 mm and a length of 5 cm (eg Symmetry C18, Waters)

Mobile phase:

    Mobile phase A: 6 nM sodium hexanes sulfonate monohydrate solution with 0.05% phosphoric acid

    Mobile Phase B: Methanol

    Gradient system Time (minutes) Mobile phase A% Mobile phase B% 0 56 44 5 56 44 13 20 80 13.1 56 44 15 56 44

Detector: UV absorbance photometer (wavelength 239nm)

Flow rate: 1.5 mL / min

Injection volume: 10 uL

Column Temperature: 45 ℃

Analytical Conditions (Conducting Materials of Hydrochlorothiazide Group)

Column: A column filled with octasilylated silica gel for liquid chromatograph with a particle diameter of 5 um in a stainless tube with an inner diameter of about 4.6 mm and a length of 5 cm (e.g. Symmetry C18, Waters)

Mobile phase:

    Mobile phase A: Acetonitrile: Methanol = 3: 1 (v / v)

    Mobile phase B: Formic acid: Water = 5: 995 (v / v)

    Gradient system Time (minutes) Mobile phase A% Mobile phase B% 0 3 97 5 3 97 14 36 64 20 90 10 25 3 97 28 3 97

Detector: UV absorbance photometer (wavelength 275nm)

Flow rate: 1.0 mL / min

Injection volume: 10 uL

Column temperature: 35 ℃

Changes in Lead Compounds of Lozatan, Amlodipine and Hydrochlorothiazide sample Early Light exposure, 1.2 million lux 50 ℃, HDPE bottle packaging
28 days storage Rojatan
cause
Leading substance
(%) Amlodipine
Leading substance
(%) Hydrochlorothiazide group
Leading material (%) Rozatan origin
Leading material (%) Amlodipine
Leading material (%) Hydrochlorothiazide group
Leading material (%) Rojatan
cause
Leading material (%) Amlodipine
Leading material (%) Hydrochlorothiazide
cause
Leading material (%) Example 1 0.01 0.01 0.04 0.02 0.10 0.09 0.05 0.09 0.11 Example 2 0.02 0.01 0.06 0.03 0.12 0.08 0.05 0.07 0.12 Comparative Example 1 0.01 0.03 0.04 0.03 0.86 0.34 0.04 1.12 1,45 Comparative Example 2 0.04 0.05 0.11 0.09 0.78 0.43 0.55 1.36 1.98

As can be seen from the table above, the lozatan, amlodipine and hydrochlorothiazide fixed dose combination formulations prepared by the methods of Examples 1 and 2 were prepared for rozatan, amlodipine and hydrochloro under severe conditions by light or heat. All three components of the thiazide were found to be very stable without significant change in the analogues. However, in the formulations of Comparative Example 1 and Comparative Example 2 prepared by simply mixing the three components, it was confirmed that the amount of generation of the flexible substance increased by more than 10 times compared to Examples 1 and 2 in all three components. This shows that the fixed dose combination formulations of the present invention have significantly higher stability over time compared to the fixed dose combination formulations prepared by the simple mixing method.

Claims (16)

As active ingredients,
Lozatan or a pharmaceutically acceptable salt thereof;
Amlodipine or a pharmaceutically acceptable salt thereof; And
Hydrochlorothiazide,
The active ingredients are each filled in a capsule in an independent separation layer,
Fixed dose combination formulation for the prevention or treatment of cardiovascular diseases.
The fixed dose combination formulation of claim 1, wherein the separation layer is in tablet form.
The fixed dose combination formulation of claim 2, wherein the tablet is coated with a pharmaceutically acceptable polymer.
The fixed dose combination formulation of claim 1, wherein the pharmaceutically acceptable salt of rozatan is rozatan potassium.
The fixed dose combination formulation of claim 1, wherein the pharmaceutically acceptable salt of amlodipine is amlodipine camsylate.
The fixed dose combination formulation of claim 1, wherein the pharmaceutically acceptable salt of amlodipine is amlodipine besylate.
The fixed dose combination formulation of claim 1, wherein the rojatan or a pharmaceutically acceptable salt thereof is included in an amount in the range of 25 mg to 200 mg.
The fixed dose combination formulation of claim 1, wherein said amlodipine or a pharmaceutically acceptable salt thereof is included in an amount in the range of 2.5 mg to 10 mg.
The fixed dose combination formulation of claim 1, wherein the hydrochlorothiazide is included in an amount in the range of 6.25 mg to 25 mg.
The fixed dose combination formulation of claim 1, wherein the separation layer comprises a pharmaceutically acceptable excipient and the active ingredient and excipient are used in a weight ratio of 1: 0.25 to 1: 20.
The group of claim 1, wherein the pharmaceutically acceptable excipient is composed of crospovidone, sodium starch glyconate, croscarmellose sodium, low-substituted hydroxypropyl cellulose, starch, alginic acid or its sodium salt, and mixtures thereof. A fixed dose combination formulation, characterized in that it comprises a disintegrant selected from.
The fixed dose combination formulation of claim 1, wherein said amlodipine or a pharmaceutically acceptable salt thereof reaches a dissolution rate of at least 80% within 30 minutes after the start of the dissolution test.
The fixed dose combination formulation of claim 1, wherein the hydrochlorothiazide reaches a dissolution rate of at least 80% within 30 minutes after the start of the dissolution test.
The fixed dose combination formulation of claim 1, wherein the cardiovascular disease is selected from the group consisting of angina pectoris, hypertension, arterial spasm, deep vein, cardiac hypertrophy, cerebral infarction, congestive heart failure and myocardial infarction.
a) mixing or granulating rojatan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and then tableting to obtain a rojatan tablet;
b) mixing or granulating amlodipine or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient and then tableting to obtain an amlodipine tablet;
c) mixing or granulating the hydrochlorothiazide and the pharmaceutically acceptable excipient and then tableting to obtain a hydrochlorothiazide tablet; And
d) filling the rojatan tablets, amlodipine tablets and hydrochlorothiazide tablets into the same hard capsule,
A method of making a fixed dose combination formulation for the prevention or treatment of cardiovascular diseases.
16. The fixed dose combination formulation of claim 15, further comprising coating the tablet obtained in one or more of steps a), b) and c) with a pharmaceutically acceptable polymer. Manufacturing method.

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